Transcutaneous auricular vagal nerve stimulation for consciousness recovery in patients with prolonged disorders of consciousness (TAVREC): study protocol for a multicenter, triple-blind, randomized controlled trial in China.

INTRODUCTION: Prolonged disorders of consciousness (pDoC) are a catastrophic condition following brain injury with few therapeutic options. Transcutaneous auricular vagal nerve stimulation (taVNS), a safe, non-invasive intervention modulating thalamo-cortical connectivity and brain function, is a possible treatment option of pDoC. We developed a protocol for a randomised controlled study to evaluate the effectiveness of taVNS on consciousness recovery in patients with pDoC (TAVREC). METHODS AND ANALYSIS: The TAVREC programme is a multicentre, triple-blind, randomised controlled trial with 4 weeks intervention followed by 4 weeks follow-up period. A minimum number of 116 eligible pDoC patients will be recruited and randomly receive either: (1) conventional therapy plus taVNS (30 s monophasic square current of pulse width 300 µs, frequency of 25 Hz and intensity of 1 mA followed by 30 s rest, 60 min, two times per day, for 4 weeks); or (2) conventional therapy plus taVNS placebo. Primary outcome of TAVREC is the rate of improved consciousness level based on the Coma Recovery Scale-Revised (CRS-R) at week 4. Secondary outcomes are CRS-R total and subscale scores, Glasgow Coma Scale score, Full Outline of UnResponsiveness score, ECG parameters, brainstem auditory evoked potential, upper somatosensory evoked potential, neuroimaging parameters from positron emission tomography/functional MRI, serum biomarkers associated with consciousness level and adverse events. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Reference number: 2023-SR-392). Findings will be disseminated in a peer-reviewed journal and presented at relevant conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073950.

A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility.

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.

Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial.

Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted. Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted. Design, Setting, and Participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023. Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone). Main Outcomes and Measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components. Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences. Conclusions and Relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

The association of insomnia with long COVID: An international collaborative study (ICOSS-II).

OBJECTIVE: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection. METHODS: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety. RESULTS: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p < .001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66). CONCLUSIONS: The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID.

Development of an innovative minimally invasive primate spinal cord injury model: A case report.

Spinal cord injury (SCI) animal models have been widely created and utilized for repair therapy research, but more suitable experimental animals and accurate modeling methodologies are required to achieve the desired results. In this experiment, we constructed an innovative dorsal 1/4 spinal cord transection macaque model that had fewer severe problems, facilitating postoperative care and recovery. In essence, given that monkeys and humans share similar genetics and physiology, the efficacy of this strategy in a nonhuman primate SCI model basically serves as a good basis for its prospective therapeutic use in human SCI.

Subtyping at-risk adolescents for predicting response toward insomnia prevention program.

BACKGROUND: Previous study has shown that a brief cognitive-behavioral prevention insomnia program could reduce 71% risk of developing insomnia among at-risk adolescents. This study aimed to evaluate the differential response to insomnia prevention in subgroups of at-risk adolescents. METHODS: Adolescents with a family history of insomnia and subthreshold insomnia symptoms were randomly assigned to a 4-week insomnia prevention program or nonactive control group. Assessments were conducted at baseline, 1 week, and 6- and 12-month after the intervention. Baseline sleep, daytime, and mood profiles were used to determine different subgroups by using latent class analysis (LCA). Analyses were conducted based on the intention-to-treat approach. RESULTS: LCA identified three subgroups: (a) insomnia symptoms only, (b) insomnia symptoms with daytime sleepiness and mild anxiety, and (c) insomnia symptoms with daytime sleepiness, mild anxiety, and depression. The incidence rate of insomnia disorder over the 12-month follow-up was significantly reduced for adolescents receiving intervention in subgroup 3 compared with the controls (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.13-0.99; p = .049) and marginally for subgroup 2 (HR = 0.14; 95% CI: 0.02-1.08; p = .059). In addition, adolescents who received intervention in subgroups 2 and 3 had a reduced risk of excessive daytime sleepiness (subgroup 2: adjusted OR [AdjOR] = 0.45, 95% CI: 0.23-0.87; subgroup 3: AdjOR = 0.32, 95% CI: 0.13-0.76) and possible anxiety (subgroup 2: AdjOR = 0.47, 95% CI: 0.27-0.82; subgroup 3: AdjOR = 0.33, 95% CI: 0.14-0.78) compared with the controls over the 12-month follow-up. CONCLUSIONS: Adolescents at risk for insomnia can be classified into different subgroups according to their psychological profiles, which were associated with differential responses to the insomnia prevention program. These findings indicate the need for further phenotyping and subgrouping at-risk adolescents to develop personalized insomnia prevention.

School-Based Sleep Education Program for Children: A Cluster Randomized Controlled Trial.

Insufficient sleep contributes negatively to child developmental processes and neurocognitive abilities, which argues the need for implementing interventions to promote sleep health in children. In this study, we evaluated the effectiveness of a multimodal and multilevel school-based sleep education program in primary school children using a cluster randomized controlled design. Twelve schools were randomly assigned to either the sleep education or nonactive control groups. The sleep education group included a town hall seminar, small class teaching, leaflets, brochures, and a painting competition for children. Parents and teachers were invited to participate in a one-off sleep health workshop. Parental/caregiver-reported questionnaires were collected at baseline and 1-month follow-up. A total of 3769 children were included in the final analysis. There were no significant improvements observed in the sleep-wake patterns, daytime functioning, and insomnia symptoms between the two groups at follow-up, whereas the intervention group had significantly improved parental sleep knowledge than the controls (paternal: adjusted mean difference: 0.95 [95% confidence interval (CI): 0.18 to 1.71]; maternal: adjusted mean difference: 0.87 [95% CI: 0.17 to 1.57]). In addition, children receiving the intervention had a lower persistence rate of excessive beverage intake (adjusted odds ratio: 0.49 [95% CI: 0.33 to 0.73]), and experienced greater reductions in conduct problems (adjusted mean difference: 0.12 [95% CI: 0.01 to 0.24]) compared with the controls at 1-month of follow-up. Moreover, a marginally significant reduction for emotional problems in the intervention group was also observed (adjusted mean difference: 0.16 [95% CI: -0.00 to 0.32]). These findings demonstrated that school-based sleep education was effective in enhancing parental sleep knowledge and improving behavioral outcomes in children, but not sufficient in altering the children's sleep-wake patterns and sleep problems.

Intermittent theta burst stimulation to the left dorsolateral prefrontal cortex improves cognitive function in polydrug use disorder patients: a randomized controlled trial.

Background: Polydrug abuse is common among opioid users. Individuals who use both heroin and methamphetamine (MA) have been shown to experience a wide range of cognitive deficits. Previous research shows that repetitive transcranial magnetic stimulation (rTMS) can change cerebral cortical excitability and regulate neurotransmitter concentration, which could improve cognitive function in drug addiction. However, the stimulation time, location, and possible mechanisms of rTMS are uncertain. Methods: 56 patients with polydrug use disorder were randomized to receive 20 sessions of 10 Hz rTMS (n = 19), iTBS (n = 19), or sham iTBS (n = 18) to the left DLPFC. All patients used MA and heroin concurrently. Cognitive function was assessed and several related proteins including EPI, GABA-Aα5, IL-10, etc. were quantified by ELISA before and after the treatment. Results: Baseline RBANS scores were lower than normal for age (77.25; IQR 71.5-85.5). After 20 treatment sessions, in the iTBS group, the RBANS score increased by 11.95 (95% CI 0.02-13.90, p = 0.05). In particular, there were improvements in memory and attention as well as social cognition. Following treatment, serum EPI and GABA-Aα5 were reduced and IL-10 was elevated. The improvement of immediate memory was negatively correlated with GABA-Aα5 (r = -0.646, p = 0.017), and attention was positively correlated with IL-10 (r = 0.610, p = 0.027). In the 10 Hz rTMS group, the improvement of the RBANS total score (80.21 ± 14.08 before vs.84.32 ± 13.80 after) and immediate memory (74.53 ± 16.65 before vs.77.53 ± 17.78 after) was statistically significant compared with the baseline (p < 0.05). However, compared with the iTBS group, the improvement was small and the difference was statistically significant. There was no statistically significant change in the sham group (78.00 ± 12.91 before vs.79.89 ± 10.92 after; p > 0.05). Conclusion: Intermittent theta burst stimulation to the left DLPFC may improve cognitive function in polydrug use disorder patients. Its efficacy appears to be better than that of 10 Hz rTMS. The improvement of cognitive function may be related to GABA-Aα5 and IL-10. Our findings preliminarily demonstrate the clinical value of iTBS to the DLPFC to augment neurocognitive recovery in polydrug use disorders.

The relationship between physical activity and depression among community-dwelling adults in Wuhan, China.

Background: While the association between physical activity (PA) and depression has been established, there is limited research on the effect of PA on the risk of depression among Chinese individuals. Thus, this study aimed to investigate the relationship between PA and depression among Chinese individuals. Methods: We used a stratified random sampling approach to recruit participants from five urban districts in Wuhan, China. A total of 5,583 permanent residents aged 18 years or older completed questionnaires, which included the International Physical Activity Questionnaire Short Form (IPAQ-SF) to measure PA, and the 9-item Patient Health Questionnaire (PHQ-9) to evaluate depressive symptoms. To control for potential confounders, multiple logistic regression was employed to assess the association of PA with depression. Results: The depression group had significantly lower weekly PA levels, measured in metabolic equivalent of task-minutes per week (MET-min/w), compared to the non-depression group [1,770 (693-4,200) MET-min/w vs. 2,772 (1,324-4,893) MET-min/w, p < 0.001]. In the fully adjusted model, the moderate and high PA level groups had lower odds ratios (ORs) for depressive symptoms compared to the low PA level group [OR (95% confidence interval (CI)) = 0.670 (0.523-0.858), 0.618 (0.484-0.790), respectively]. Among males, moderate and high levels of PA were associated with lower risk of depression compared to low PA levels [OR (95% CI) = 0.417 (0.268-0.649), 0.381 (0.244-0.593), respectively]. However, this association was not observed in females [OR (95% CI) = 0.827 (0.610-1.121), 0.782 (0.579-1.056), respectively]. The study found a significant interaction between PA levels and gender in relation to depression (P for interaction = 0.019). Conclusion: The findings suggest a negative association between PA and risk of depressive symptoms, indicating that moderate to high levels of PA may serve as a protective factor against depressive symptoms.

Ex vivo manufacturing of platelets: beyond the first-in-human clinical trial using autologous iPSC-platelets.

Platelet transfusion is a common clinical approach to providing platelets to patients suffering from thrombocytopenia or other ailments that require an additional platelet source. However, a stable supply of platelet products is challenged by aging societies, pandemics, and other factors. Many groups have made extensive efforts toward the in vitro generation of platelets for clinical application. We established immortalized megakaryocyte progenitor cell lines (imMKCLs) from human induced pluripotent stem cells (iPSCs) and achieved clinical-scale manufacturing of iPSC-derived platelets (iPSC-PLTs) from them by identifying turbulent flow as a key physical condition. We later completed the iPLAT1 study, the first-in-human clinical trial using autologous iPSC-PLTs. This review summarizes current findings on the ex vivo generation of iPSC-PLTs that led to the iPLAT1 study and beyond. We also discuss new insights regarding the heterogeneity of megakaryocytes and the implications for the ex vivo generation of iPSC-PLTs.

[Spatial-temporal differentiation and influencing mechanism of green development efficiency in three major urban agglomerations in Zhejiang Province, China.] / 浙江三大城市群绿色发展效率时空分异及影响机理.

Improving the green development efficiency of the three major urban agglomerations in Zhejiang is an important way to faster build the pilot demonstration area of beautiful China. Based on county panel data from 2000 to 2019 of 41 counties (cities) included in the three major urban agglomerations, we combined the super-efficiency SBM model with window analysis to evaluate the efficiency, and used spatial econometric analysis method to study the spatial distribution and the differences in regional difference. Furthermore, the fixed panel fixed effect model was used to explore the differential influencing mechanism. The results showed that green development efficiency of the three major urban agglomerations increased gradually with fluctuations during the study period. The distribution of efficiency values gradually shifted from a situation of 'high in the north and low in the south' to a 'relatively common and coordinated' development in the various regions. There was a significant spatial agglomeration effect in green development efficiency of the three major urban agglomerations, but it presented fluctuating phenomenon among cities which were at the similar level. The average green development efficiency of central Zhejiang urban agglomeration was the highest. The development within the three major urban agglomerations was relatively stable. The annulus Hangzhou Bay urban agglomeration came next, with stable development. The Wenzhou-Taizhou coastal urban agglomeration was the lowest, but the efficiency enhancement was the largest. The increases in population density, along with the proportion of added value of tertiary industry in GDP, per capita industrial added value, local fiscal expenditures, education expenditures and per capita actual use of foreign capital could improve the efficiency of green development. However, the increases in industrial electricity consumption and fixed asset investment in kennels would inhibit the improvement of green development efficiency. The impacts of per capita industrial added value, local fiscal expenditure, education expenditure and per capita actual use of foreign capital on urban agglomerations were heterogeneous among different cities.

Sense of Alienation and Its Associations With Depressive Symptoms and Poor Sleep Quality in Older Adults Who Experienced the Lockdown in Wuhan, China, During the COVID-19 Pandemic.

OBJECTIVE: To examine the epidemiology of sense of alienation (SoA) and its associations with depressive symptoms and poor sleep quality (PSQ) in Chinese older adults who experienced lockdown during the COVID-19 pandemic. BACKGROUND: There is a dearth of data on SoA in older adults during the COVID-19 pandemic. METHODS: Altogether, 543 community-dwelling older adults (50+ years) were recruited via the three-tier mental health network in Wuhan, China, and completed an online questionnaire in April 2020, the first month after the reopening of Wuhan. SoA, depressive symptoms, and sleep quality were measured by using the General Social Alienation Scale, Depression Anxiety and Stress Scale, and a single standardized question, respectively. RESULTS: The prevalence of SoA was 52.3% (95% confidence interval: 48.1-56.5%). Factors associated with higher levels of SoA were religious belief (ß = 1.960, P = .024), monthly family income<4000 RMB (ß = 1.405, P = .022), unemployment (ß = 1.217, P = .039), fair or poor physical health (ß = 2.202, P = .002), never and sometimes receiving community support (ß = 2.297, P < .001 and ß = 3.417, P < .001), perceiving a low possibility of a cure for COVID-19 (ß = 2.379, P < .001), and affirmative and unsure fear of COVID-19 patients (ß = 2.025, P = .007 and ß = 1.101, P = .027). After adjusting for sociodemographic and pandemic-related variables, a one-SD increment in the SoA score was significantly associated with depressive symptoms (Odd Ratio [OR] = 5.59, P < .001) and poor sleep quality (Odd Ratio = 2.00, P < .001). CONCLUSION: Over half of the older adults who experienced lockdown felt alienated, and SoA was independently associated with their depressive symptoms and PSQ. Efforts are warranted to address SoA in older adults who experienced lockdown during the pandemic.

Nightmares mediate the association between traumatic event exposure and suicidal ideation in frontline medical workers exposed to COVID-19.

BACKGROUND: Trauma experience increases the risk of suicidal ideation, but little is known about potentially psychological mechanisms underlying this relationship. This study aims to examine the relationship between coronavirus disease 2019 (COVID-19)-related traumatic event (CTE) exposure and suicidal ideation among hospital workers, and identify mediating roles of sleep disturbances in this relationship. METHODS: Workers in seven designated hospitals in Wuhan, China, were invited to participate in an online survey from May 27, 2020, to July 31, 2020. Participants completed a self-report questionnaire to evaluate demographic characteristics, level of CTE exposures, nightmare frequency, insomnia severity, symptoms of depression and anxiety, and suicidal ideation. A series of correlation analyses were performed, and a mediation model was generated to examine correlations between CTE exposure, sleep disturbances, and suicidal ideation. RESULTS: A total of 16,220 hospital workers were included in the final analysis, 13.3% of them reported suicidal ideation in the past month. CTE exposure was significantly associated with insomnia severity, nightmare frequency, and suicidal ideation. After controlling potential confounders, nightmares but not insomnia, depression, or anxiety were shown to be independent risk factors for suicidal ideation. Pathway analyses showed that the relationship between CTE exposure and suicidal ideation was fully mediated by nightmares (proportion mediated 66.4%) after adjusting for demographic characteristics and psychological confounders. LIMITATIONS: Cross-sectional design precluded the investigation of causal relationships. CONCLUSIONS: CTE exposure increases risk of hospital workers' suicidal ideation that is mediated by nightmares, suggesting nightmares intervention might be considered as a component when developing suicide prevention strategies.

The trajectories and associations of eveningness and insomnia with daytime sleepiness, depression and suicidal ideation in adolescents: A 3-year longitudinal study.

BACKGROUND: Eveningness and insomnia are highly comorbid and closely related to psychopathology in adolescents. We aimed to prospectively investigate the trajectories and associations of eveningness and insomnia with daytime functioning, depression and suicidal risk in adolescents. METHODS: A 3-year longitudinal study was conducted among 414 Chinese adolescents. The associations of eveningness and insomnia with daytime functioning, depression and suicidal ideation were analyzed using logistic regressions. RESULTS: The prevalence rates of eveningness were similar at baseline and follow-up (19.3% vs 22.5%; p = 0.27), while the prevalence of insomnia increased at follow-up (29.2% vs 40.8%; p < 0.001). Among those eveningness adolescents (n=80) at baseline, 46.2% remained as stable evening-type at follow-up, and among those insomnia adolescents (n=121) at baseline, 64.5% had persistent insomnia at follow-up. Logistic regressions showed that stable, incident, and resolved eveningness were associated with excessive daytime sleepiness (EDS) at follow-up, while only persistent and incident insomnia increased the risk of EDS. Persistent and incident insomnia, as well as stable eveningness were independently associated with depression at follow-up. Persistent and incident insomnia, but not eveningness, were associated with suicidal ideation. LIMITATIONS: The outcome assessments were based on self-reported questionnaires and the sample size is modest. CONCLUSIONS: Persistent eveningness and insomnia are significantly associated with greater risks of EDS and depression in adolescents, while both persistent and incident insomnia, but not eveningness, increased the risk of suicidal ideation. These findings underscore the importance of addressing sleep and circadian factors in the management of adolescent mood and daytime functioning.

Objective sleep duration is associated with cognitive deficits in primary insomnia: BDNF may play a role.

Study Objectives: Objective sleep duration has been linked to insomnia severity. However, cognitive functions of people with insomnia with different sleep durations have been seldom addressed. Brain-derived neurotrophic factor (BDNF) has an important role in cognitive function and has been linked to clinical insomnia recently. The present study aimed to evaluate the comprehensive cognitive functions in people with primary insomnia with different objective sleep durations, and further examine the involvement of peripheral BDNF. Methods: Fifty-seven people with insomnia were subdivided into short sleep duration (SSD, sleep time < 6 hr) group and normal sleep duration (NSD, sleep time ≥ 6 hr) group based on polysomnography data. Twenty-nine healthy controls (HC) were matched on age, gender, and education. Cognitive function was assessed using a comprehensive and sensitive neuropsychological test battery. Both objective and subjective insomnia statuses were estimated. Serum BDNF level was measured using enzyme-linked immune sorbent assay. Results: Compared with HC, the SSD group showed impaired neuropsychological performances in spatial span, brief visuospatial memory test, fluency, managing emotions, and continuous performance tests. In contrast, NSD had bad performance only in brief visuospatial memory test and continuous performance tests, and relatively better than SSD group in the latter test. People with SSD insomnia but not NSD had decreased BDNF levels compared with HC, and neuropsychological performance was positively correlated with BDNF levels only in SSD group. Conclusions: Primary insomnia was associated with impaired neuropsychological performance, and the impairment might be related to decreased objective sleep duration. In addition, decreased peripheral BDNF might mediate the impaired cognitive functions of people with insomnia with SSD.

ADRB2 gene polymorphism modulates the retention of fear extinction memory.

Individual differences in regulation of fear and extinction memory play significant roles in the aetiology development of post-traumatic stress disorder (PTSD). Previous animal based studies showed that the activity of ß-adrenergic receptors (ß-ARs) are involved in memory modulation. However in humans it is not clear that whether genetic variability in ß-ARs contributes to individual differences of fear and extinction memory. In the current study, we investigated the role of a common single-nucleotide polymorphism of ß2-adrenergic receptor (ADRB2) gene in fear memory acquisition, fear memory extinction, extinction recall and fear generalization in human participants. Ninety-one male participants were exposed to a Pavlovian fear conditioning and their fear responses were assessed by the skin conductance response. Participants were genotyped for a polymorphism (rs2400207) located within the promoter region of the human ADRB2. Differences between genotypes were observed in the extinction memory recall test but not in fear acquisition, extinction learning and fear generalization. Particularly, A-allele carriers of rs2400707 displayed successful retention of extinction memory and prevented the return of fear during recall test. The results revealed the involvement of human noradrenergic system in the retention of extinction memory and genetic variability in this system may underlie individual differences in PTSD. Furthermore, rs2400207 polymorphism of ADRB2 gene may play a key role in the treatment efficacy of PTSD and can be a basis for future studies investigating a personalized medicine for fear memory related disorders.

Association between sleep duration during pregnancy and gestational diabetes mellitus: a meta-analysis.

OBJECTIVE: Sleep is critical for glucose metabolism. Pregnant women often have sleep disturbances and extreme sleep duration. Investigations of the relationship between sleep duration during pregnancy and gestational diabetes mellitus (GDM) have reported inconsistent results. The present study aimed to meta-analyze the relationship between sleep duration during pregnancy and GDM risk. METHODS: We performed a systematic search of the PubMed, ISI Web of Science, and PsycINFO databases for studies that were published up to October 2017, that reported associations between sleep duration during pregnancy and GDM risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated as the effect sizes for all studies. Heterogeneity and potential publication biases were assessed. RESULTS: A total of 4366 papers were retrieved, among which seven studies assessed the relationship between sleep duration during pregnancy and GDM development. The seven articles included 18,203 subjects at baseline and 1294 GDM cases during follow-up. Compared to normal sleep duration, extreme sleep duration during early and middle pregnant stages had a close relationship with GDM based upon pooled data from prospective and cross-sectional studies. Prospective results showed that long sleep duration during pregnancy was a risk factor for GDM, but not short sleep duration. Publication biases were found when analyzing the relationship between extreme sleep duration and GDM. CONCLUSIONS: Extreme sleep duration during pregnancy is closely associated with GDM. Moreover, long but not short sleep duration can predict the risk of developing GDM. These findings remind us of the importance of sleep duration control during pregnancy and help optimize early strategies for the prevention of GDM.

A ß1-tubulin-based megakaryocyte maturation reporter system identifies novel drugs that promote platelet production.

During maturation, megakaryocytes (MKs) express ß1-tubulin (TUBB1) and rearrange their microtubule components to enlarge, form proplatelets, and eventually release platelets. The development of a platform to identify in vitro conditions that would efficiently promote MK development could potentially enable large-scale platelet production. Here, we show that an immortalized MK cell line (imMKCL) genetically modified to express the ß1-tubulin-Venus reporter provides a practical system to efficiently monitor the in vitro production of platelet-like particles (PLPs). The Venus transgene was inserted downstream of the TUBB1 locus in imMKCLs using CRISPR/Cas9, and the expression was visualized by Venus fluorescence intensity. This imMKCL reporter line was then used for high-throughput drug screening. We identified several compounds that significantly improved the efficiency of PLP production in vitro under feeder-free conditions and showed a significant tendency to recover platelets in vivo in a mouse thrombocytopenia model induced by anti-GPIbα antibody administration. Interestingly, most of these compounds, including a WNT signaling pathway inhibitor, Wnt-C59, antagonized the aryl hydrocarbon receptor (AhR) to increase PLP production, confirming the crucial role of AhR inhibition in MK maturation. Consistently, small interfering RNA treatment against AhR increased the Venus intensity and PLP production. TCS 359, an FLT3 inhibitor, significantly increased PLP production independently of FLT3 or AhR. This study highlights the usefulness of the ß1-tubulin reporter MK line as a useful tool to study the mechanisms underlying thrombopoiesis and to identify novel inducers of ex vivo platelet production.

Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis.

Sleep disturbances and dementia are two common and significant health problems in older adults. Investigations suggest that sleep disturbances might increase the risk of dementia. The aim of the present study was to systematically review and meta-analyze the predictive roles of overall sleep disturbances, their subtypes (e.g., insomnia, sleep disordered breathing [SDB]), and other sleep problems (e.g., excessive daytime sleepiness, sleep-related movement disorder, circadian rhythm sleep disorder, and nonspecific sleep problems) in incident all-cause dementia and Alzheimer's disease (AD) and vascular dementia subtypes. We performed a systematic search of the PubMed, EMBase, ISI Web of Science, and PsycINFO databases for longitudinal studies that were published up to October 28, 2016. A total of 12,926 papers were retrieved. Eighteen longitudinal studies that included 246,786 subjects at baseline and 25,847 dementia cases after an average 9.49 y of follow-up were eligible for inclusion. Compared with individuals without sleep disturbances, subjects who reported sleep disturbances had a higher risk of incident all-cause dementia, AD, and vascular dementia. The subgroup analysis showed that insomnia increased the risk of AD but not vascular or all-cause dementia. In contrast, SDB was associated with a higher incidence of all-cause dementia, AD, and vascular dementia. This meta-analysis suggests that sleep disturbances may predict the risk of incident dementia. Moreover, insomnia was associated only with incident AD, and SDB was a risk factor of all-cause dementia, AD, and vascular dementia. However, sleep disturbances were evaluated mainly based on self-reports, and some confounders may mediate the relationship between sleep disturbances and dementia. Therefore, the results should be further validated. In summary, these findings may help identify individuals who are at risk for dementia and optimize early prevention strategies.